The implantation of artificial devices and organs is always accompanied by the traumatic disruption of tissue. Long term success is currently hampered by an unacceptable incidence of infection in the inflamed tissue around the prosthesis. This proposal is designed to investigate one aspect of the pathogenesis of such infection. We will examine the in vitro and in vivo interaction of selected prosthetic biomaterials with cellular and humoral components of the traumatic wound. We hypothesize that contact between certain biomaterials and neutrophils and/or plasma will cause initial activation and resultant depletion of the host defenses against infection. The activation and resultant depletion of the host defenses against infection. The activation of the cellular (neutrophilic) component will result in release of activated intermediates of oxidative metabolism and of lysosomal constituents which can induce tissue necrosis. Concomitantly, the interaction will render the neutrophil incapable of effective further response to infection. Additionally, we hypothesize that activation of the humoral component will cause utilization and depletion of complement components necessary for effective host-microbe interaction. Specifically, the proposed work will characterize the changes that take place in neutrophil and plasma as a result of in vitro exposure to those biomaterials commonly used in prosthetic devices; then, using an animal model, we will determine whether or not these defects also are produced around prosthetic biomaterial in vivo. The study will further document that these defects are associated with increased infectivity in the periprosthetic space in proportion to the observed activation and subsequent impairment of neutrophil and plasma function. Modification of the biomaterials by coating them with substances (laminin, fibronectin, vitronectin, capillary endothelial cells) known to be less damaging to neutrophils or less activating to complement will then be carried out. Unmodified and modified biomaterials can then be compared with respect to the damage induced by contact with cellular and humoral host defenses in vitro as well as their infectivity of the periprosthetic space in vivo. This investigation should not only enhance our understanding of the mechanisms of postimplantation infections but it should also help in the design and predictive testing of future biomaterials by providing in vitro correlates of infectivity.
Showing the most recent 10 out of 15 publications
